Recent advances in polymerase engineering have made it possible to synthesize nucleic acid polymers with a wide range of chemical modifications, including xeno-nucleic acid (XNA) polymers with backbone structures that are not found in nature1-3. While this technological advance generated significant interest in XNA polymers as a synthetic polymer for future applications in molecular medicine, nanotechnology, and materials science4-7, the current generation of XNA polymerases function with markedly lower activity than their natural counterparts8, 9. The prospect of developing synthetic polymerases with improved activity and more diverse functions has driven a desire to apply molecular evolution as a strategy for altering the catalytic properties of natural polymerases10, 11. Compartmentalized self-replication (CSR) and compartmentalized self-tagging (CST) are examples of technologies that have been developed to evolve polymerases with expanded substrate specificity1, 12. However, these methods use the parent plasmid as template for the primer-extension reaction, which limits the range of polymerase functions to enzymes that promote DNA-templated synthesis. Thus, progress in the realm of synthetic biology is hindered by the lack of effective XNA polymerase. Accordingly, there is a need for methods of developing XNA polymerases with activity comparable to their natural counterparts.